Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Antiplatelet Agents
Introduction
Platelets are the smallest blood cells in the human body, normally numbering 150–350 × 109/L, and play a central role in the normal homeostatic process of hemostasis and thrombosis. As first described in the 18th century, platelets are involved in nearly all aspects of vascular occlusive disease. This includes the disruption of platelet- and fibrin-rich atherosclerotic plaques, which lead to further platelet aggregation and deposition causing thrombus formation and, possibly, clinically relevant thrombotic events. Antiplatelet agents modulate the role of platelets in these delicate processes. Thus a detailed understanding of platelet function and antiplatelet pharmacology is essential for the practicing vascular specialist.
Normal Platelet Function and Platelet Activation
Normally platelets circulate without interacting with the blood vessel wall. This delicate balance is modulated by the interaction of platelets with the endothelium. The endothelium releases nitric oxide and prostacyclin to prevent platelet aggregation. In addition, endothelial cells express ADPase, which degrades adenosine diphosphate (ADP) released from activated platelets, further inhibiting platelet aggregation. A platelet life span ranges from 8 to 10 days.
Platelets are the essential components of primary hemostasis. Primary hemostasis is defined as the early stages of hemostasis to prevent blood loss. When vessel injury occurs, the subendothelium is exposed. Exposed tissue factor, subendothelial collagen, von Willebrand factor, and fibronectin interact with molecules expressed on the platelet surface (α 2 β 1, glycoprotein Ib/IX, and α 5 β 1 ). These interactions induce a conformational change in platelet morphology and stimulate platelet granule release of ADP and thromboxane A2. Exposure of ADP receptors on activated platelets induces platelet aggregation by cross-linking ADP molecules. Thromboxane A2 induces vasoconstriction and further recruitment of platelets to the site of injury. Platelet activation also results in the expression of glycoprotein IIb/IIIa (GP-IIB/IIIA) on the platelet surface. GP-IIB/IIIA ligates divalent fibrinogen to bridge platelets, thus promoting aggregation. The platelet aggregates are woven into a fibrin mesh formed by the cleavage of fibrinogen by thrombin. This platelet plug forms the basis for the later stages of hemostasis. Antiplatelet agents modulate various steps in these intricate processes ( Fig. 42.1 ).
Thromboxane Inhibitors
Aspirin
Mechanism of Action
Aspirin is the most commonly used antiplatelet agent. It is a nonselective, irreversible cyclooxygenase enzyme (COX) inhibitor. It irreversibly acetylates COX-1, interrupting the production of prostaglandin H2 and the production of thromboxane A2 (TXA2) to prevent platelet aggregation. , At higher doses, COX-2 is also inhibited, promoting the anti-inflammatory effect of aspirin.
Indications and Dose
Aspirin is indicated for the prevention of cardiovascular events in patients with established coronary disease, peripheral arterial occlusive disease, or cerebrovascular occlusive disease. More recently, the use of aspirin for primary prevention in patients without an established cardiovascular risk profile has been scrutinized, but there is no consensus recommendation regarding aspirin use for primary prevention of adverse cardiovascular events. ,
Aspirin doses range from 75 to 325 mg/daily. Non-enteric-coated aspirin can achieve platelet inhibition approximately 1 hour after ingestion. Enteric-coated aspirin may achieve platelet inhibition at 3 to 4 hours after ingestion. Chewing aspirin can result in inhibition as rapidly as 20 minutes after ingestion and is independent of the enteric coating of the pill.
Side-Effect Profile
The most common side effects involve the gastrointestinal (GI) tract and range from dyspepsia to gastritis and ulcers, which may lead to bleeding and/or perforation. Helicobacter pylori infection may predispose to a higher risk of GI bleed. The risk of bleeding is estimated to be between 1% and 3% per year and increases with the addition of other antiplatelet agents (e.g., clopidogrel) or anticoagulants (e.g., warfarin).
Allergy to aspirin is a rare phenomenon (∼0.3% of patients). Bronchospasm can occur in patients allergic to aspirin, and this stands as a contraindication to aspirin administration. Allergy to aspirin may be more common in patients with asthma, urticaria, nasal polyps, or chronic rhinitis and thus administration should be undertaken with caution.
Perioperative Management
Aspirin may be discontinued 7 to 10 days before surgery in those at moderate to high risk for bleeding and a low estimated risk for cardiovascular events while off the medication. Otherwise, aspirin can be continued perioperatively in patients undergoing diagnostic or therapeutic interventions at low risk for bleeding. In patients undergoing vascular surgery, aspirin can be safely continued in the perioperative period. , In cases such as carotid interventions, aspirin should be initiated preoperatively in patients not already on antiplatelet therapy.
Thienopyridines (Adenosine Diphosphate Receptor Antagonists)
Clopidogrel
Mechanism of Action
Clopidogrel is a prodrug that is activated by the hepatic cytochrome-450 (CYP450) enzyme system (mainly CYP2C19 ). It irreversibly inhibits P2Y12 (a key ADP receptor) on the platelet surface. Because it requires activation, the onset to therapeutic inhibition can be variable and can be influenced by genetic polymorphisms of the CYP450 system.
Indications and Dose
Clopidogrel is indicated for use in patients with unstable angina/non-ST-elevated myocardial infarction (UA/NSTEMI), ST-segment myocardial infarction (STEMI), recent myocardial infarction, recent cerebrovascular accident (CVA), or established peripheral arterial occlusive disease. Off-label use includes adjunctive therapy after percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, or peripheral artery percutaneous transluminal angioplasty. For patients with symptomatic carotid artery stenosis or with aspirin intolerance, clopidogrel is frequently used.
The usual daily dose of clopidogrel is 75 mg. The time to platelet inhibition (the onset of action) is dose-dependent and may take to the second day of therapy to detect activity at the usual daily dose. During periods that require more rapid therapeutic levels (e.g., coronary stenting), a bolus dose between 300 and 600 mg of clopidogrel may be administered. This provides a more rapid onset of platelet inhibition (typically about 2 hours). ,
Side-Effect Profile
The main side effect of clopidogrel is bleeding, and this can occur at any site. The incidence of severe GI hemorrhage is estimated to be 2%. Other, less common side effects include pruritus and epistaxis.
Perioperative Management
Clopidogrel should be discontinued 7 to 10 days prior to surgery (minimum of 5 days) before elective surgery, except in patients with coronary stents who have not completed a full course of dual antiplatelet therapy.
Drug–Drug Interactions
Clopidogrel’s antiplatelet effect may be influenced by other drugs metabolized via the CYP450 enzyme system. Specifically, proton-pump inhibitors, which are inhibitors of CYP2C19, may lessen the ability of clopidogrel to inhibit platelet aggregation. This interaction may not be clinically relevant for most patients; however, current recommendations are to avoid the administration of CYP2C19 inhibitors concomitantly with clopidogrel, whenever possible.
Clopidogrel Resistance
The most important CYP450 isoenzyme involved in clopidogrel metabolism (and thus activation) is CYP2C19 . Patients with certain variant CYP2C19 alleles (CYP2C19∗2 or CYP2C19∗3) may have reduced conversion of clopidogrel to the active metabolite compared with wild-type alleles (CYP2C19∗1), which may result in reduced platelet inhibition. , This may result in a higher rate of adverse cardiovascular events. Additional polymorphisms in ABCB1 (a gene encoding the P-glycoprotein pump responsible for transporting molecules across intracellular and extracellular membranes) and CYP3A4 can also reduce the effectiveness of clopidogrel and have been linked to adverse events. However, there is insufficient evidence to recommend routine genetic testing. Tests are available to determine the CYP2C19 genotype and may be used to determine therapeutic strategy (i.e., alternative treatment may be considered if the patient is identified as a poor metabolizer). Functional testing (e.g., the VerifyNow P2Y12 assay) can be done after the initiation of treatment to determine a patient’s clinical responsiveness to clopidogrel (i.e., assess for a non-responder) and to further optimize antiplatelet strategy. , The GRAVITAS trial, however, did not show any benefit in individualizing the dose of clopidogrel in patients based on functional testing results.
Ticagrelor
Mechanism of Action
Ticagrelor reversibly and noncompetitively binds the ADP P2Y12 receptor reducing platelet aggregation. Due to the reversible nature of the receptor binding, the levels of platelet inhibition may fluctuate due to serum concentration of drug. It is metabolized via the cytochrome P450 enzyme system (the major isoenzyme is CYP3A4 ).
Indications and Dose
Ticagrelor is indicated for acute coronary syndrome (ACS) to reduce the rate of cardiovascular death, myocardial infarction (MI), and stroke. Ticagrelor reduces the rate of in-stent thrombosis in patients stented during treatment of ACS. Off-label indications include use in patients with UA/NSTEMI and an allergy to or intolerance of aspirin.
Ticagrelor is initiated with a loading dose of 180 mg followed by a maintenance dose of 60–90 mg twice daily (t½ = 7 to 9 hours). Time to maximal inhibition of platelet aggregation is approximately 2 hours.
Side-Effect Profile
Side effects are similar to clopidogrel. Unique side effects specific to ticagrelor include elevated serum uric acid levels and transient dyspnea. Ticagrelor should, therefore, be used with caution in patients with a history of gouty arthritis or baseline hyperuricemia. , Dyspnea is typically self-limited and resolves within 1 week. It does not require any specific intervention nor does it warrant cessation of therapy unless the patient is intolerant to the medication-associated dyspnea.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here